DEFEROX

Deferasirox is an iron chelator and the first oral medication FDA approved for chronic iron overload in patients receiving long term blood transfusions.

For the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

Deferasirox is an

Oral active chelator that is selective for iron (as Fe3+).

It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio.

Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox.

The clinical significance of these decreases is uncertain.

The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose.

CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%).

Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion.

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces.

Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose).

The mean elimination half-life ranged from 8-16 hours following oral administration.

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Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported.

In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption.

In one pediatric case, a dose of 2-3 times the prescribed dose for 6 days resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support.

Single doses of deferasirox up to 80 mg per kg per day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted.

In healthy subjects, single doses of up to 40 mg per kg per day with the tablet for oral suspension formulation were tolerated.

Early signs of acute overdose are digestive effects such as abdominal pain, diarrhea, nausea, and vomiting.

Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation.

An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment.

There is no specific antidote for deferasirox.

In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.

Deferasirox is contraindicated in patients with

Estimated GFR less than 40 mL/min/1.73 m 2; Poor performance status; High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy); Advanced malignancies; Platelet counts less than 50 x 10 9 /L; Known hypersensitivity to deferasirox or any component of deferasirox.

GFR less than 40 mL/min/1.73 m 2.

Patients with poor performance status.

Patients with high-risk myelodysplastic syndrome (MDS).

Patients with advanced malignancies.

Patients with platelet counts less than 50 x 10 9 /L. Known hypersensitivity to deferasirox or any component of deferasirox.

Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m is 14 mg per kg (calculated to nearest whole tablet ) once daily.

Initial dose for patients with eGFR greater than 60 mL/min/1.73 m is 7 mg per kg (calculated to nearest whole tablet) once daily.

See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment. 2.1Transfusional Iron Overload Deferasirox tablets therapy should only be considered when a patient has evidence of chronic transfusional iron overload.

The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L. Prior to starting therapy, or increasing dose, evaluate: Serum ferritin level Obtain renal function Obtain serum creatinine in duplicate (due to variations in measurements).

Calculate the estimated glomerular filtration rate (eGFR).

Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).

Obtain urinalyses and serum electrolytes to evaluate renal tubular function.

Serum transaminases and bilirubin

Baseline auditory and ophthalmic examinations Initiating Therapy: The recommended initial dose of deferasirox tablets for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m is 14 mg per kg body weight orally, once daily.

Calculate doses (mg per kg per day) to the nearest whole tablet.

Changes in weight of pediatric patients over time must be taken into account when calculating the dose.

Monitor serum ferritin monthly and adjust the dose of deferasirox tablets, if necessary, every to 6 months based on serum ferritin trends.

Use the minimum effective dose to achieve a trend of decreasing ferritin Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.

In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered.

Doses above 28 mg per kg are not recommended.

Adjust dose based on serum ferritin levels If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction especially if the deferasirox tablets dose is greater than 17.5 mg/kg/day.

If the serum ferritin falls below 500 mcg/L, interrupt deferasirox tablets therapy to minimize the risk of overchelation, and continue monthly monitoring.

Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.

Use the minimum effective dose to maintain iron burden in the target range.

Monitor blood counts, liver function, renal function and ferritin monthly.

Interrupt deferasirox tablets for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently.

Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. 2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Deferasirox tablets therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. Prior to starting therapy, obtain: LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy Serum ferritin level on at least 2 measurements 1-month apart Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements).

Baseline auditory and ophthalmic examinations Initiating Therapy: The recommended initial dose of deferasirox tablets for patients with eGFR greater than 60 mL/min/1.73 m is 7 mg per kg body weight orally once daily.

If the baseline

LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation.

Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.

Use the minimum effective dose to achieve a trend of decreasing ferritin.

LIC every 6 months.

After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day. If after 6 months of therapy, the LIC is to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day. When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.

Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake.

Consider dose interruption until oral intake and volume status are normal.

Restart treatment when the

LIC rises again to more than 5 mg Fe/g dw. 2.3Administration Swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. Take deferasirox tablets on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories).

Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard).

Do not take deferasirox tablets with aluminum-containing antacid products.

For patients who have difficulty swallowing whole tablets, deferasirox tablets may be crushed and mixed with soft foods (e.g., yogurt or applesauce) immediately prior to use and administered orally.

Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet.

The dose should be immediately and completely consumed and not stored for future use.

For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox tablets, the dose should be about 30% lower, rounded to the nearest whole tablet.The table below provides additional information on dosing conversion to deferasirox tablets.

Tablets for oral suspension (white round tablet) Deferasirox Tablets (film coated yellow oval tablet) Transfusion-Dependent Iron Overload Starting Dose 20 mg/kg/day 14 mg/kg/day Titration Increments to 10 mg/kg 3.5 to 7 mg/kg Maximum Dose 40 mg/kg/day 28 mg/kg/day Non-Transfusion-Dependent Thalassemia Syndromes Starting Dose 10 mg/kg/day 7 mg/kg/day Titration Increments to 10 mg/kg 3.5 to 7 mg/kg Maximum Dose 20 mg/kg/day 14 mg/kg/day 2.4Use in Patients With Baseline Hepatic or Renal Impairment Patients with Baseline Hepatic Impairment Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary.

Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%.

Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox tablets.

Do not use deferasirox tablets in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m 2.

For patients with renal impairment (eGFR to 60 mL/min/1.73 m 2 ), reduce the starting dose by 50% .

Exercise caution in pediatric patients with eGFR between and 60 mL/minute/1.73 m 2.

If treatment is needed, use the minimum effective dose and monitor renal function frequently.

Individualize dose titration based on improvement in renal injury. 2.5Dose Modifications for Decrease in Renal Function While on Deferasirox Tablets Deferasirox tablets is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2.

For decreases in renal function while receiving deferasirox tablets, modify the dose as follows: Transfusional Iron Overload Adults: If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg. Pediatric Patients (ages 2 years to 17 years): Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week.

Interrupt deferasirox tablets for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently.

Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal.

Avoid use of other nephrotoxic drugs.

In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox tablets use.

Use the minimum effective deferasirox tablets dose and monitor renal function more frequently, by evaluating tubular and glomerular function.

Titrate dosing based on renal injury.

Consider dose reduction or interruption and less nephrotoxic-therapies until improvement of renal function.

If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox tablets to prevent severe and irreversible renal injury.

Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2.

Non-Transfusion-Dependent Thalassemia Syndromes Adults

If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg. Pediatric Patients (ages 10 years -17 years): Reduce the dose by 3.5 mg per kg if eGFR decreases by greater than 33% below.

Deferasirox 90 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '90' on another side.

They are available in bottles of 30 tablets (NDC 69539-073-30).

They are available in bottles of 1000 tablets (NDC 69539-073-99).

Deferasirox 180 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '180' on another side.

They are available in bottles of 30 tablets (NDC 69539-074-30).

They are available in bottles of 1000 tablets (NDC 69539-074-99).

Deferasirox 360 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '360' on another side.

They are available in bottles of 30 tablets (NDC 69539-075-30).

They are available in bottles of 1000 tablets (NDC 69539-075-99).

Store deferasirox tablets at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) .

Protect from moisture.

There are no studies with the use of deferasirox in pregnant women to inform drug-associated risks.

Administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on a mg/m 2 basis.

No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m 2 basis.

Deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown.All pregnancies had a background risk of birth defect, loss, or other adverse outcomes.

However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on an mg/m 2 basis).

These doses resulted in maternal toxicity but no fetal harm was observed.

In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis).

Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis).

The safety and effectiveness of deferasirox have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload.

Safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload.

Pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias.

Seventy percent of these patients had beta-thalassemia.

In those clinical studies, 173 children (ages to < 12 years) and 119 adolescents (ages to < 17 years) were exposed to deferasirox.

Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

The safety and effectiveness of Deferasirox have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (NTDT) syndromes.

Safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in NTDT syndromes.

Pediatric approval for treatment of

NTDT syndromes with liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and NTDT.

Use of deferasirox in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients.

In general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs.

Acute kidney injury, and acute liver injury and failure has occurred in pediatric patients.

In a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury.

Higher rates of renal

AEs have been identified among pediatric patients receiving deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when their serum ferritin values were less than 1,000 mcg/L.

Monitoring recommendations for all pediatric patients with Transfusional Iron Overload and NTDT It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation.

Monitor renal function by estimating

GFR using an eGFR prediction equation appropriate for pediatric patients and evaluate renal tubular function.

Monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion.

Use the minimum effective dose.

Interrupt deferasirox in pediatric patients with transfusional iron overload, and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently.

Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal.

Evaluate the risk benefit profile of continued deferasirox use in the setting of decreased renal function.

Avoid use of other nephrotoxic drugs.

Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses.

In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence.

Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m 2 approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU ® (deferasirox) tablets.

However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Four hundred thirty-one patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting.

Two hundred twenty-five of these patients were between and 75 years of age while were greater than or equal to 75 years of age.

The majority of these patients had myelodysplastic syndrome (MDS) (n=393).

In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients.

Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment.

Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox tablets for oral suspension therapy.